KR20220021207A - 이소골 형성 부작용 경감으로 치료효과가 증진된 골형성 단백질-9, 10의 변이체 및 이를 포함하는 약학적 조성물 - Google Patents
이소골 형성 부작용 경감으로 치료효과가 증진된 골형성 단백질-9, 10의 변이체 및 이를 포함하는 약학적 조성물 Download PDFInfo
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Abstract
본 발명은 BMP-9의 변이체 및 이의 유도체에 관한 것으로, 상기 변이체는 야생형 BMP-9대비 내피세포 특이적인 신호전달은 자극하되 골형성과 관련한 신호전달은 자극하지 않아, 종양, 심혈관질환, 섬유증 질환, 염증성 질환, 대사성 질환, 자가면역 질환을 포함한 다양한 질환에 대한 치료 효과는 높이며 부작용은 낮출 수 있는 효과가 있다.
Description
본 발명은 BMP-9의 변이체 및 이의 유도체에 관한 것으로, 더 상세하게는 종양, 심혈관질환, 섬유증 질환, 대사성 질환을 포함한 다양한 질병, 장애 및 질환을 치료에서 이소골 형성 부작용 경감으로 치료 효과가 증진된 BMP-9의 변이체 및 이의 유도체에 관한 것이다.
BMP-9은 기존에 알려진 BMP 수용체와 결합하는 것이 아닌, 독특한 수용체와 결합하는 특성을 가지고 있고 세포내 여러 과정에서의 다양한 역할 때문에 다른 BMP 류와 구분된다. 예컨대, BMP-9은 간에서 생성되어 지질대사를 억제할 수 있고, 간의 포도당생성을 제어할 수 있으며, 심혈관계에서는 내피세포의 성장과 이동을 조절하고, 심근모세포의 섬유화를 억제한다. 특히 심혈관계에서는 BMP-10과 함께 내피세포의 ALK-1수용체 및 BMPR-II, Endoglin과 결합하여 혈관의 항상성 및 혈압조절에도 관계한다. 다수의 문헌에서 해당 수용체의 결손 등에 의해 발생한 폐동맥고혈압, 심근섬유증에 대해 BMP-9 및 BMP-10을 적용하였을 때 해당 증상이 경감하는 것을 보고한바, 치료용 물질로서의 BMP-9의 활용성이 높음을 알 수 있다. 또한 종양 종류에 따라서 전립선암 세포의 사멸을 유도할 수 있고 골조직에서는 골형성분화를 조절할 수 있는 강력한 BMP들 중 하나이다. 또한, 인슐린 감수성 개선 효과도 있어 새로운 항-당뇨병 또는 항-비만 치료제 타깃으로 잠재성이 높은 것으로 알려져 있다.
이에 따라 BMP-9를 포함한 성장인자를 타깃으로 하는 새로운 치료용 약제 개발을 위해, 야생형 성장인자를 기반으로 일부 아미노산을 치환, 도입, 제거하여 돌연변이를 제작함으로서, 성장인자의 생물학적 활성을 높인 시도가 있었다(WO 2010/065439). 그러나, BMP-9을 포함한 성장인자를 생물치료제로서 직접 사용하는 것과 연관된 문제점은 이소골 형성 및 변형 성장인자 작용이 동시에 발현된다는 것이다. 이는 BMP-9를 포함한 성장인자의 수용체의 복잡성 때문으로, 아직까지 이소골 형성과 관련된 부작용을 경감한 사례는 부족하다. BMP-9 및 BMP-10의 수용체는 주로 혈관 내피세포에 존재하는데, Alk-1 및 BMPR-II의 리간드로서 작용하면서 혈관기능조절에 관련한다고 알려져 있다. 즉 BMPR-II가 ALK-1과 복합체를 형성하고, 선택적으로 BMP-9, 10과 반응하는데, 이 때 수용체가 결손되거나 BMP-9, 10이 결핍되는 경우 빈발하는 질환은 폐동맥고혈압, 심근 섬유증이다. 특히 BMP-9은 내피세포에 직접 작용하여 혈관 내벽의 integrity를 증진시켜 혈관 안정성을 증진함으로써 혈관세포사멸이나 신생혈관형성을 억제한다. 특히 다른 류의 BMP, 예컨데 BMP-2,4,6 등과 달리 BMP-9은 골형성을 일으키지 않는 저농도에서도 내피세포의 활성을 촉진시킨다고 알려져 있다. 그러나 고농도 적용시에는 BMP-9 역시 이소골 형성을 유도할 수 있어, 실제 임상에 적용시에는 이소골 형성기능은 제어된 상태의 변이체 적용이 필요한 상황이다.
또한 성장인자의 특성상 야생형의 체내 반감기가 매우 짧은 것도 치료제로 상용화하기 어려운 점으로 지적되어 왔다. (Kharitonenkov, A. et al., Journal of Clinical Investigation, 115:1627-1635, 2005). BMP-9의 생체 내 반감기는 마우스에서 10분 내지 1시간, 원숭이에서 1.5시간 내지 2시간으로 짧기 때문에 이를 치료제로 개발한다면 매일 투여해야 하는 단점이 있다. 현재까지 재조합 단백질의 생체 내 반감기를 증가시키기 위하여 다양한 기술들이 보고되었다. 단백질에 고분자 물질인 폴리에틸렌 글리콜(polyethylene glycol, PEG)을 연결하여 분자량을 증가시켜, 신장 배설을 억제함으로써 체내 잔류 시간을 증가시킨 예가 있다(WO 2012/066075). 또한, 성장인자 분자에 인간 알부민에 결합하는 지방산을 융합시켜 반감기를 향상시킨 예도 있다 (WO 2012/010553). 나아가, 인간 성장인자 수용체 단독 또는 베타-클로토와의 복합체에 특이적으로 결합하는 아고니스트 항체를 만들어 성장인자의 작용기전과 동일한 약리학적 활성을 나타내면서 반감기를 증가시킨 예도 있다(WO 2012/170438). 또한, 성장인자 분자에 면역글로불린 IgG의 Fc를 연결한 지속형 융합 단백질을 만들어 반감기를 향상시킨 예도 있다(WO 2013/188181).
이에, 본 발명자들은 이소골 형성을 억제하고, 작용 시간을 연장시키기 위한 BMP9 기반의 치료용 변이체 단백질 연구에 매진한 결과, 일부 변이체의 경우 이소골 형성이 저해되고 생체 내 반감기가 증가하는 것을 확인함으로써 본 발명을 완성하였다.
Kharitonenkov, A. et al., Journal of Clinical Investigation, 115:1627-1635, 2005
본 발명은 이소골 형성 부작용이 경감된 골형성 단백질-9 (BMP-9) 변이체; 및 이의 융합체를 제공하는 것을 목적으로 한다.
본 발명은 또한 상기 골형성 단백질-9 (BMP-9) 변이체; 및 이의 융합체의 다양한 치료적 용도를 제공하는 것이다.
상기 목적을 달성하기 위하여, 본 발명은 서열번호 2 내지 29로 구성된 군에서 선택되는 어느 하나의 아미노산 서열로 표시되는 골형성 단백질-9 (BMP-9) 변이체를 제공한다.
본 발명은 또한, 상기 BMP-9 변이체에 면역글로불린의 Fc 단편이 연결되어 있는 BMP-9 변이체-Fc 융합 단백질을 제공한다.
본 발명은 또한, 상기 BMP-9 변이체; 또는 상기 BMP-9 변이체-Fc 융합 단백질을 유효성분으로 포함하는 종양 치료용 약학적 조성물을 제공한다.
본 발명은 또한, 상기 BMP-9 변이체; 또는 상기 BMP-9 변이체-Fc 융합 단백질을 유효성분으로 포함하는 염증성 질환 치료용 약학적 조성물을 제공한다.
본 발명은 또한, 상기 BMP-9 변이체; 또는 상기 BMP-9 변이체-Fc 융합 단백질을 유효성분으로 포함하는 대사성 질환 치료용 약학적 조성물을 제공한다.
본 발명은 또한, 상기 BMP-9 변이체; 또는 상기 BMP-9 변이체-Fc 융합 단백질을 유효성분으로 포함하는 자가면역 질환 치료용 약학적 조성물을 제공한다.
본 발명에서는 BMP-9의 치료효과를 극대화하고 부작용은 현저히 감소시킬 수 있도록 변이체를 설계하여 포유류 세포에서 고효율로 발현 및 정제하였고, 이와 더불어 BMP-9의 혈중 반감기를 연장하고자 면역글로불린의 Fc부위와 융합된 융합 단백질을 추가로 제작하였다. 이들 변이체와 융합 단백질은 시험관 내 및 동물실험을 통해 종양, 섬유증, 심폐혈관질환, 비만 및 지방간 등 다양한 질환에 대해 우수한 치료 효과를 발휘하는바, 이들 질환 치료를 위한 신규한 치료제로 활용이 가능할 것이다.
도 1은 본 발명의 개요를 보여주는 모식도이다.
도 2는 BMP-9, BMP-9 변이체 및 Fc와 융합된 BMP-9가 도입되는 발현벡터를 나타낸다.
도 3a는 발현 및 정제된 BMP-9 변이체의 SDS-PAGE, western blot 결과이고, 도 3b는 발현 및 정제된 Fc와 융합된 BMP-9의 SDS-PAGE, western blot 결과이다.
도 4는 발현 및 정제된 BMP-9 및 변이체의 혈관내피세포에 대한 신호전달 활성(도 4a) 및 골형성신호전달 활성(도 4b)을 보여준다.
도 5는 심근섬유세포에서의 BMP-9 변이체의 섬유증 관련 마커의 억제 효과를 보여주는 결과이다.
도 6은 혈액에서 정제된 BMP-9및 Fc가 융합된 BMP-9의 혈중 농도를 측정한 그래프이다.
도 2는 BMP-9, BMP-9 변이체 및 Fc와 융합된 BMP-9가 도입되는 발현벡터를 나타낸다.
도 3a는 발현 및 정제된 BMP-9 변이체의 SDS-PAGE, western blot 결과이고, 도 3b는 발현 및 정제된 Fc와 융합된 BMP-9의 SDS-PAGE, western blot 결과이다.
도 4는 발현 및 정제된 BMP-9 및 변이체의 혈관내피세포에 대한 신호전달 활성(도 4a) 및 골형성신호전달 활성(도 4b)을 보여준다.
도 5는 심근섬유세포에서의 BMP-9 변이체의 섬유증 관련 마커의 억제 효과를 보여주는 결과이다.
도 6은 혈액에서 정제된 BMP-9및 Fc가 융합된 BMP-9의 혈중 농도를 측정한 그래프이다.
다른 식으로 정의되지 않는 한, 본 명세서에서 사용된 모든 기술적 및 과학적 용어들은 본 발명이 속하는 기술분야에서 숙련된 전문가에 의해서 통상적으로 이해되는 것과 동일한 의미를 갖는다. 일반적으로, 본 명세서에서 사용된 명명법 및 이하에 기술하는 실험 방법은 본 기술분야에서 잘 알려져 있고 통상적으로 사용되는 것이다.
본 발명에서는 BMP-9 유전자를 클로닝하고, 이에 대한 다양한 변이체를 제작한 후, 이를 포유류 세포 (CHO 세포 및 인간태아신장세포주)에서 발현 및 정제하여, 종양, 염증성 질환, 심혈관 질환, 대사성 질환 및 자가면역 질환에 효과 좋은 BMP-9 변이체를 선별하였으며, 이에 Fc를 융합시켜 혈중 반감기를 증가시킬 수 있었다. 구체적으로 본 발명에서는 BMP-9 단백질 중 Wrist epitope 및 Knuckle epitope에 해당하는 아미노산 서열에서 한 개 또는 여러 개의 아미노산을 치환하여 수용체 결합력을 조절함으로써 최적의 BMP-9 치료효과를 유도하도록 설계하였다. 즉, 본 발명에서는 내피세포 특유의 신호전달은 유지하면서도 이소골 형성은 10분의 1 이하로 억제할 수 있는 변이체를 선별하는 것을 목적으로 하였으며, 본 발명에 따른 변이체가 마우스의 심근섬유세포 (C2C12)에서 이소골 형성력이 야생형에 비해 현저히 감소되어 있음을 Alkaline phosphatase 활성과 Alizarin Red 염색법을 통해 확인할 수 있었다.
따라서, 본 발명은 일 관점에서 서열번호 1 내지 29로 구성된 군에서 선택되는 어느 하나의 아미노산 서열로 표시되는 골형성 단백질-9 (BMP-9) 또는 그 변이체에 관한 것이고, 다른 관점에서 상기 골형성 단백질-9 (BMP-9) 또는 그 변이체;에 면역글로불린의 Fc 단편이 연결되어 있는 BMP-9 변이체-Fc 융합 단백질에 관한 것이다.
서열번호 1의 아미노산 서열은 BMP-9의 야생형을 나타내는 것으로, 이는 하기와 같이 볼드체로 표시된 신호서열과 밑줄로 표시된 Pro-BMP-9의 서열을 모두 포함한다. 이중 FFPLADDVTPTKHAIVQTLVHLKF 서열은 ALK-1과 결합하는 영역으로 전체 BMP-9의 구조로 보았을 때 Wrist epitope에 속하고, KVGKACCVPTKLSPISVLYK 서열은 BMP-2수용체와 결합하는 Knuckle epitope에 속한다.
MAWVWTLLFLMAAAQSIQA KPLQSWGRGSAGGNAHSPLGVPGGGLPEHTFNLKMFLENVKVDFLRSLNLSGVPSQDKTRVEPPQYMIDLYNRYTSDKSTTPASNIVRSFSMEDAISITATEDFPFQKHILLFNISIPRHEQITRAELRLYVSCQNHVDPSHDLKGSVVIYDVLDGTDAWDSATETKTFLVSQDIQDEGWETLEVSSAVKRWVRSDSTKSKNKLEVTVESHRKGCDTLDISVPPGSRNLPFFVVFSNDHSSGTKETRLELREMISHEQESVLKKLSKDGSTEAGESSHEEDTDGHVAAGSTLARRKRSAGAGSHCQKTSLRVNFEDIGWDSWIIAPKEYEAYECKGGCFFPLADDVTPTKHAIVQTLVHLKFPTKVGKACCVPTKLSPISVLYKDDMGVPTLKYHYEGMSVAECGCR
상기 야생형 BMP-9 서열에서 도출된 변이체 서열은 서열번호 2 내지 서열번호 29 중 어느 하나의 아미노산 서열로 표시될 수 있으며, 이들 변이체는 야생형 BMP-9 서열에서 일부 아미노산 서열이 치환된 것이다. 그러나, 본 발명에 따른 변이체는 서열번호로 표시된 특정 아미노산 서열에 한정되지 않으며, 해당 아미노산 서열과 균등한 것으로 볼 수 있는 아미노산 서열이 본 발명의 권리범위에 속함은 당업자에게 자명할 것이다. 예를 들어, 서열번호 2에서 335번째 아미노산은 야생형에 비해 Asp에서 Ala로 치환되어 있는데, 이와 같은 변이체의 핵심적 구성을 제외한 나머지 서열 중 일부가 BMP-9의 단백질의 기능과 구조에 영향을 주지 않도록 돌연변이 되어 있는 경우라면 해당 변이체도 본 발명의 권리범위에 속함은 당업자에게 자명할 것이다. 따라서, 본 발명은 서열번호 2 내지 서열번호 29중 어느 하나의 아미노산 서열에서, 변이체의 핵심이 되는 아미노산의 치환 이외의 나머지 서열의 적어도 95% 이상, 적어도 90% 이상, 적어도 80% 이상, 적어도 70% 이상 상동성이 인정되는 변이체도 본 발명의 권리범위에 속하는 것으로 이해될 것이다.
한편, 본 발명의 변이체는 골형성 단백질의 다른 subtype, 예컨데 BMP-7, 10에도 적용이 가능할 것이다.
본 발명에서는, 야생형 또는 변이형의 BMP-9의 혈중 반감기를 증진시키고자, 면역글로불린의 Fc 단편을 융합시킬 수 있는데, 상기 면역글로불린의 Fc 단편은 서열번호 30의 아미노산 서열로 표시되는 것을 특징으로 할 수 있으나, 이에 한정되지는 않는다. 한편, 면역글로불린의 Fc 단편 이외에도 단백질에 융합되어 혈중 반감기를 증가시킬 수 있는 다양한 펩타이드나 단백질, 예컨대 알부민,의 융합이 가능하다.
본 발명에 있어서, 상기 면역글로불린의 Fc 단편은 상기 골형성 단백질-9 (BMP-9) 또는 그 변이체의 N-말단 또는 C-말단에 연결돌 수 있다.
본 발명에 있어서, 상기 골형성 단백질-9 (BMP-9) 또는 그 변이체; 및 면역글로불린의 Fc 단편은 링커에 의해 연결되어 있는 것을 특징으로 할 수 있으나, 이에 한정되지는 않는다.
본 발명에 있어서, 상기 링커는 서열번호 31의 아미노산 서열로 표시되는 것을 특징으로 할 수 있으나, 이에 한정되지는 않는다.
본 발명에 있어서, 상기 BMP-9 변이체-Fc 융합 단백질은 서열번호 32 또는 서열번호 33의 아미노산 서열로 표시되는 것을 특징으로 할 수 있으나, 이에 한정되지는 않는다.
본 발명에 따른 BMP-9 또는 변이체, 또는 이의 융합 단백질은 치료용, 진단용, 또는 연구용 시약 (reagent)으로 활용될 수 있으나, 치료적 용도로 활용하는 것이 가장 바람직하다.
구체적으로, 본 발명은 상기 골형성 단백질-9 (BMP-9) 또는 그 변이체; 또는 상기 BMP-9 변이체-Fc 융합 단백질을 유효성분으로 포함하는 종양 치료용 약학적 조성물을 제공한다.
본 발명에 있어서, 상기 종양은 유방암, 폐암, 결장암, 대장암, 간암, 췌장암, 뇌종양, 전립선암, 피부암, 골육종 및 혈액암으로 구성된 군에서 선택되는 1종 이상인 것을 특징으로 할 수 있으나, 이에 한정되지는 않는다.
본 발명은 또한, 상기 골형성 단백질-9 (BMP-9) 또는 그 변이체; 또는 상기 BMP-9 변이체-Fc 융합 단백질을 유효성분으로 포함하는 염증성 질환 치료용 약학적 조성물을 제공한다.
본 발명에 있어서, 상기 염증성 질환은 지방간염, 간염 및 장염으로 구성된 군에서 선택된 1종 이상인 것을 특징으로 할 수 있으나, 이에 한정되지는 않느다.
본 발명은 또한, 상기 골형성 단백질-9 (BMP-9) 또는 그 변이체; 또는 상기 BMP-9 변이체-Fc 융합 단백질을 유효성분으로 포함하는 대사성 질환 치료용 약학적 조성물을 제공한다.
본 발명에 있어서, 상기 대사성 질환은 비만, 체중 감소, 당뇨병, 죽상경화증, 동맥경화증, 심폐질환, 신경 질환, 알츠하이머 질환, 인지 장애, 산화적 스트레스, 피부 질환, 피부 노화, UV 조사에 의한 손상, 고혈압, 고콜레스테롤혈증(LDL, HDL, VLDL), 고지혈증(트리글리세라이드), 면역 결핍, 암 및 대사성 증후군으로 구성된 군에서 선택된 1종 이상인 것을 특징으로 할 수 있으나, 이에 한정되지는 않는다.
본 발명에 있어서, 상기 심폐질환은 심근경색, 고혈압, 폐동맥고혈압, 심근섬유증 및 폐섬유증으로 구성된 군에서 선택되는 1종 이상인 것을 특징으로 할 수 있으나, 이에 한정되지는 않는다.
본 발명은 또한, 상기 골형성 단백질-9 (BMP-9) 또는 그 변이체; 또는 상기 BMP-9 변이체-Fc 융합 단백질을 유효성분으로 포함하는 자가면역 치료용 약학적 조성물을 제공한다.
본 발명에 있어서, 상기 자가면역 질환은 인슐린-의존성 당뇨병, 다발성 경화증, 자가면역 뇌척수염, 류마티스성 관절염, 골관절염, 중증 근무력증, 갑상선 염, 포도막염, 하시모토 갑상선염, 갑상샘 중독증, 악성 빈혈, 자가면역 위축 위염, 자가면역 용혈성 빈혈, 특발성 백혈구 감소, 원발성 담관 경화증, 알코올성/비알코올성 지방간염, 염증성 장질환, 크론병, 궤양성 장질환, 건선, 쇼그렌 증후군, 경피증, 베게너 육아종증, 다발근육염, 피부근육염, 원판상 LE 및 전신 홍반 루푸스로 구성된 군에서 선택된 1종 이상인 것을 특징으로 할 수 있으나, 이에 한정되지는 않는다.
상기 치료 목적을 위하여, 본 발명에서의 활성형의 BMP-9 변이체 및 유도체가 단독으로도 투여될 수 있지만 약학적 조성물 (제형)로 투여됨이 바람직하며 멸균 제형으로 투여되는 것이 바람직하다.
본 발명에 있어서, 상기 약학적 조성물은 주사제, 경구투여용 제제, 수용액, 현탁액, 유탁액 등과 같은 액제 (예를 들어, 주사용), 캡슐, 과립, 정제, 점막투여제제 구성된 군에서 선택되는 어느 하나의 제형으로 제제화되는 것을 특징으로 할 수 있으나, 이에 한정되는 것은 아니다. 이들 제제는 당분야에서 제제화에 사용되는 통상의 방법 또는 Remington's Pharmaceutical Science(최근판), Mack Publishing Company, Easton PA 에 개시되어 있는 방법으로 제조될 수 있으며 각 질환에 따라 또는 성분에 따라 다양한 제제로 제제화될 수 있다.
한편, 본 발명의 약학적 조성물은 상기 치료용 BMP-9변이체, 유도체 이외에 약제학적으로 허용가능한 담체를 1 종 이상 더 포함할 수 있다. 약제학적으로 허용 가능한 담체는 식염수, 멸균수, 링거액, 완충 식염수, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1성분 이상을 혼합하여 사용할 수 있다.
본 발명의 약학적 조성물은 필요에 따라 약제학적으로 허용가능한 보조제를 추가로 함유하는 것을 특징으로 할 수 있다. 상기 보조제는 부형제, 희석제, 분산제, 완충제, 항균성 보존제, 정균제, 계면활성제, 결합제, 윤활제, 산화방지제, 증점제 및 점도개질제로 구성된 군에서 선택되는 하나 이상일 수 있으나, 이에 한정되는 것은 아니다.
본 발명에 따른 약학적 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구 투여(예를 들어, 정맥 내, 피하, 근육내, 복강 내 또는 국소에 적용)할 수 있으며, 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율 및 질환의 중증도 등에 따라 그 범위가 전문가의 소견에 따라 다양하게 변경되어 사용될 수 있다.
본 발명의 일 실시양태로서, 상기 단백질의 일회 투여량은 1 μg/kg 내지 100 ㎎/㎏, 바람직하게는 5 μg/kg 내지 50 ㎎/㎏이고, 일일 일회 또는 주 1-3회 투여하는 것을 특징으로 할 수 있으나, 투여량과 투여간격이 이에 한정되는 것은 아니다.
실시예
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지는 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.
실시예
1. 재조합 인간
proBMP
-9 및
proBMP10의
제작
인간 pre-proBMP9의 open reading frame을 포함하는 전범위의 cDNA를 pcDNA3.4 벡터에 삽입, 클론닝하였고 (도 2), 이는 DNA 시퀀싱으로 확인하였다. Pro-BMP9의 변이체는 QuickChange Site-directed mutagenesis kit을 이용하여 획득하였고, 이 또한 DNA 시퀀싱으로 확인하였다.
본 발명에서 사용된 BMP-9 야생형 및 변이체 서열은 다음과 같다.
서열번호 1. 야생형 latent BMP-9 (NIBEC-J)
MAWVWTLLFLMAAAQSIQA KPLQSWGRGSAGGNAHSPLGVPGGGLPEHTFNLKMFLENVKVDFLRSLNLSGVPSQDKTRVEPPQYMIDLYNRYTSDKSTTPASNIVRSFSMEDAISITATEDFPFQKHILLFNISIPRHEQITRAELRLYVSCQNHVDPSHDLKGSVVIYDVLDGTDAWDSATETKTFLVSQDIQDEGWETLEVSSAVKRWVRSDSTKSKNKLEVTVESHRKGCDTLDISVPPGSRNLPFFVVFSNDHSSGTKETRLELREMISHEQESVLKKLSKDGSTEAGESSHEEDTDGHVAAGSTLARRKRSAGAGSHCQKTSLRVNFEDIGWDSWIIAPKEYEAYECKGGCFFPLADDVTPTKHAIVQTLVHLKFPTKVGKACCVPTKLSPISVLYKDDMGVPTLKYHYEGMSVAECGCR
야생형 서열에서, 볼드체는 신호 펩타이드 서열, 밑줄은 Pro-BMP 서열, BMP-9 서열은 별다른 표시를 하지 않았다.
PreproBMP9을 함유한 플라스미드는 CHO-S세포주에 Polyethylene imine으로 transfection 시키고 이후 enhancer를 첨가하여 8일간 배양하였다. 발현된 ProBMP9및 ProBMP10은 웨스턴블랏 방법으로 antiBMP9항체, antiBMP10항체를 이용하여 측정하였다.
발현된 단백질을 정체하기 위해서는 1-5리터의 Conditioned media를 완충액으로 이미 평형상태에 도달한 Q-Sepharose 컬럼을 통해 분리하였다. 컬럼에 부착된 목적 단백질은 염화나트륨 gradient에 의해서 분획을 받도록 하였고, 분획된 샘플은 농축후 젤크로마토그래피를 통과하여 목적분자량에서 획득하도록 하였다. 이를 통해 획득한 단백질은 95%이상의 순도를 지니고 있음을 확인하였다.
실시예
2. 재조합 인간
proBMP
-9
변이체의
제작
BMP9이나 BMP10이 혈관내피세포의 ALK1수용체에 선택적으로 결합하고, 이로인해 심혈관계질환 치료제로서 유망하나, 이들은 여전히 중간엽세포나 Myoblast를 자극하여 골형성을 촉진할 수 있는 잠재성이 있어 치료제로 개발할 때는 해당 성격을 무력화하는 것이 필요하다. 현재까지는 어떠한 수용체가 BMP9이나 10의 골분화력에 관련하는지는 아직 밝혀지지 않았다. 본 발명의 연구자는 BMP-9의 구조중 Wrist Epitope 및 Knuckle Epitope이 주요 신호전달에 매개하는 리간드 역할을 하는 것으로 파악하였던 바, 이들 서열을 조절함으로써 내피세포 신호전달은 유지하면서도 골분화력을 억제할 수 있음을 확인하였다 (서열 1-29, 도 4). 이러한 변이체는 생체내에서도 유사한 생리활성을 지닐것으로 판단되었던 바 부작용 우려를 최소화 하면서도 치료효과를 증진시킬 수 있는 잇점을 제공할 것으로 전망되었다.
실시예3
. 내피세포에서의 BMP-
9변이체
및 유도체에 의한 신호전달
각 ProBMP9 변이체의 양은 ELISA로 측정하여 세포에 처리하였다. 혈청을 첨가하지 않은 상태에서 HUVEC세포에 상기 도출된 변이체를 지시된 농도범위로 가하였다. 8시간 처리 후 세포를 취하고 mRNA를 추출하여 ID1 및 BMPR-II의 발현을 quantitative PCR로 측정하였다. 또한 pSmad1/5/8의 발현을 위해서는 상기 세포에 무혈청 상태에서 BMP9 변이체를 처리 후 1시간후에 관찰하였다. 세포를 Lysis buffer에서 처리한 후 획득한 단백질에 대해서 항 pSmad1/5/8 항체에 대해 immunoblotting을 하여 발현량을 측정하였다. 관찰결과 (도 4) 변이체들은 ID1 및 BMPR-II을 유의적으로 증가시켰고, 증가된 양은 야생형 BMP-9대비 큰 차이를 나타내지 않았음을 확인하였다. 이는 이전의 보고에서도 확인한 대로, 혈관내피세포에서 BMP9이나 BMP10은 ALK1수용체의 리간드로 작용함을 확인할 수 있었다. 문헌에 의하면 BMP9은 순환계에서 내피세포의 이행, 증식 및 내피세포에 의한 혈관신생을 억제하는 것으로 알려져 있다.
실시예
4.
C2C12
세포배양에서의
BMP9
변이체에
의한
골분화
신호전달
마우스의 심근세포인 C2C12는 중간엽줄기세포와 유사한 분화력을 지니기 때문에 골분화력을 관찰하기위해 선택되었다. C2C12세포는 DMEM배지에서 0.25% FBS하에서 16시간 배양후에 BMP9 변이체들로 처리되었다. 이후 72시간을 추가로 배양한 후에 세포를 1% Triton X-100/PBS로 파쇄하여 얻은 단백질에 대해서 ALP 효소활성을 측정하였다. ALP효소활성은 해당 효소의 기질인 4-nitrophenyl phosphate disodium salt와 반응시켜 생성되는 수용성물질을 405nm에서 흡광도를 측정하여 확인하며, 표준물질로는 BMP-9을 구입하여 대조하였다. 관찰 결과 변이체들은 표준물질 대비 현저히 골분화력이 저하된 것을 확인할 수 있었다 (도 4). 이로써 형성된 변이체들은 상기 실시예 3에서의 혈관내피세포 신호전달은 유지하면서도 골형성력이 무력화되어 치료효과를 제공함과 동시에 이소골 형성 부작용은 없을 것으로 판단되었다.
실시예
5.
생체내에서의
BMP9
-
Fc유도체의
반감기 연장 효과
BMP-9과 BMP-9이 Fc에 융합된 유도체를 1mg/kg 용량으로 마우스의 꼬리정맥을 통해 주사한 후 일정 시간 간격으로 혈액을 채취하여 혈중 BMP-9의 양을 BMP-9 정량키트를 이용하여 측정하였다. 측정한 결과 (도 5) Fc가 결합된 BMP-9유도체 (서열번호 32-33)의 경우 현저히 증가된 혈중 농도 곡선을 획득할 수 있음을 확인하였다.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.
<110> NIBEC Co., Ltd.
Seoul National University Industry Foundation
<120> BMP-9 or BMP-10 variants with improved therapeutic effect by
reducing the side effects of ossicle formation and a
pharmaceutical composition using the same
<130> P20-B203
<160> 33
<170> KoPatentIn 3.0
<210> 1
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> Homo sapiens
<400> 1
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Asp Asp Val Thr Pro Thr
355 360 365
Lys His Ala Ile Val Gln Thr Leu Val His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 2
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 2
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Ala Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Asp Asp Val Thr Pro Thr
355 360 365
Lys His Ala Ile Val Gln Thr Leu Val His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 3
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 3
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Glu Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Asp Asp Val Thr Pro Thr
355 360 365
Lys His Ala Ile Val Gln Thr Leu Val His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 4
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 4
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Asp Glu Val Thr Pro Thr
355 360 365
Lys His Ala Ile Val Gln Thr Leu Val His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 5
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 5
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Asp Asp Val Thr Pro Thr
355 360 365
Lys His Asp Ile Val Gln Thr Leu Val His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 6
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 6
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Asp Asp Val Thr Pro Thr
355 360 365
Lys His Ala Ile Val Gln Thr Leu Val His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Glu Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 7
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 7
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Asp Asp Val Thr Pro Thr
355 360 365
Lys His Ala Ile Val Gln Thr Leu Val His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Asn Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 8
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 8
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Asp Asp Val Thr Pro Thr
355 360 365
Lys His Ala Ile Val Gln Thr Leu Val His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Gln Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 9
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 9
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Asp Asp Val Thr Pro Thr
355 360 365
Lys His Ala Ile Val Gln Thr Leu Val His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr His Trp Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 10
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 10
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Lys Ala Asp Asp Val Thr Pro Thr
355 360 365
Lys His Ala Ile Val Gln Thr Leu Val His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 11
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 11
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Asn Asp Val Thr Pro Thr
355 360 365
Lys His Ala Ile Val Gln Thr Leu Val His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 12
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 12
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Gln Asp Val Thr Pro Thr
355 360 365
Lys His Ala Ile Val Gln Thr Leu Val His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 13
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 13
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Asp Asp Val Thr Pro Thr
355 360 365
Lys His Pro Ile Val Gln Thr Leu Val His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 14
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 14
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Asp Asp Val Thr Pro Thr
355 360 365
Lys His Ala Arg Val Gln Thr Leu Val His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 15
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 15
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Asp Asp Val Thr Pro Thr
355 360 365
Lys His Ala Ile Val Gln Thr Arg Val His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 16
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 16
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Asp Asp Val Thr Pro Thr
355 360 365
Lys His His Lys Val Gln Thr Leu Val His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 17
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 17
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Asp Asp Val Thr Pro Thr
355 360 365
Lys Arg Arg Lys Val Gln Thr Leu Val His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 18
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 18
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Asp Asp Val Thr Pro Thr
355 360 365
Lys His Arg Lys Val Arg Thr Arg Val His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 19
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 19
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Asp Asp Val Thr Pro Thr
355 360 365
Lys Pro Arg Ile Val Gln Thr Leu Val His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 20
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 20
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Trp Pro Leu Ala Asp Asp Val Thr Pro Thr
355 360 365
Lys His Ala Ile Val Gln Thr Leu Val His Leu Lys Tyr Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 21
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 21
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Cys Ala Asp Asp Val Thr Pro Thr
355 360 365
Lys His Cys Ile Asp Gln Thr Leu Asp His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 22
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 22
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Asp Asp Val Thr Pro Thr
355 360 365
Lys His Ala Ile Val Gln Thr Leu Val His Leu Lys Cys Gly Gly Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 23
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 23
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Cys Ala Asp Asp Val Thr Pro Thr
355 360 365
Lys His Cys Ile Asp Gln Thr Leu Asp His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Asp Cys Cys Val Pro Thr Lys Ile Ser Pro Ile Ser Val
385 390 395 400
Leu Trp Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 24
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 24
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Asp Asp Val Thr Pro Thr
355 360 365
Lys His Ala Ile Val Gln Thr Leu Val His Leu Lys Cys Gly Gly Lys
370 375 380
Val Gly Lys Ala Cys Cys Ala Pro Thr Pro Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Trp Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 25
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 25
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Ala Asp Val Thr Pro Thr
355 360 365
Lys His Ala Ile Val Gln Thr Leu Val His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 26
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 26
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Asp Asp Val Thr Pro Thr
355 360 365
Lys His Ala Ile Val Gln Thr Leu Val His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Ala Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 27
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 27
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Glu Asp Val Thr Pro Thr
355 360 365
Lys His Ala Ile Val Gln Thr Leu Val His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 28
<211> 426
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 28
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Ala Asp Val Thr Pro Thr
355 360 365
Lys His Ala Ile Val Gln Thr Leu Val His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Ala Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg
420 425
<210> 29
<211> 24
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-9 varient
<400> 29
Phe Phe Pro Leu Ala Asp Asp Val Thr Pro Thr Lys His Ala Ile Val
1 5 10 15
Gln Thr Leu Val His Leu Lys Phe
20
<210> 30
<211> 243
<212> PRT
<213> Artificial Sequence
<220>
<223> Fc
<400> 30
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
20 25 30
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
35 40 45
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
50 55 60
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
65 70 75 80
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
85 90 95
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
100 105 110
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
115 120 125
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
130 135 140
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
145 150 155 160
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
165 170 175
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
180 185 190
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
195 200 205
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
210 215 220
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
225 230 235 240
Pro Gly Lys
<210> 31
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Linker
<400> 31
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 32
<211> 368
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-Fc fusion
<400> 32
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
20 25 30
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
35 40 45
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
50 55 60
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
65 70 75 80
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
85 90 95
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
100 105 110
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
115 120 125
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
130 135 140
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
145 150 155 160
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
165 170 175
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
180 185 190
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
195 200 205
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
210 215 220
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
225 230 235 240
Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Ser Ala Gly Ala Gly Ser His Cys Gln Lys Thr Ser Leu Arg
260 265 270
Val Asn Phe Glu Asp Ile Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys
275 280 285
Glu Tyr Glu Ala Tyr Glu Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala
290 295 300
Asp Asp Val Thr Pro Thr Lys His Ala Ile Val Gln Thr Leu Val His
305 310 315 320
Leu Lys Phe Pro Thr Lys Val Gly Lys Ala Cys Cys Val Pro Thr Lys
325 330 335
Leu Ser Pro Ile Ser Val Leu Tyr Lys Asp Asp Met Gly Val Pro Thr
340 345 350
Leu Lys Tyr His Tyr Glu Gly Met Ser Val Ala Glu Cys Gly Cys Arg
355 360 365
<210> 33
<211> 665
<212> PRT
<213> Artificial Sequence
<220>
<223> BMP-Fc fusion
<400> 33
Met Ala Trp Val Trp Thr Leu Leu Phe Leu Met Ala Ala Ala Gln Ser
1 5 10 15
Ile Gln Ala Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser Ala Gly Gly
20 25 30
Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu Pro Glu His
35 40 45
Thr Phe Asn Leu Lys Met Phe Leu Glu Asn Val Lys Val Asp Phe Leu
50 55 60
Arg Ser Leu Asn Leu Ser Gly Val Pro Ser Gln Asp Lys Thr Arg Val
65 70 75 80
Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr Thr Ser Asp
85 90 95
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe Ser Met Glu
100 105 110
Asp Ala Ile Ser Ile Thr Ala Thr Glu Asp Phe Pro Phe Gln Lys His
115 120 125
Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg His Glu Gln Ile Thr Arg
130 135 140
Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val Asp Pro Ser
145 150 155 160
His Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu Asp Gly Thr
165 170 175
Asp Ala Trp Asp Ser Ala Thr Glu Thr Lys Thr Phe Leu Val Ser Gln
180 185 190
Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu Val Ser Ser Ala Val
195 200 205
Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn Lys Leu Glu
210 215 220
Val Thr Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu Asp Ile Ser
225 230 235 240
Val Pro Pro Gly Ser Arg Asn Leu Pro Phe Phe Val Val Phe Ser Asn
245 250 255
Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu Leu Arg Glu Met
260 265 270
Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser Lys Asp Gly
275 280 285
Ser Thr Glu Ala Gly Glu Ser Ser His Glu Glu Asp Thr Asp Gly His
290 295 300
Val Ala Ala Gly Ser Thr Leu Ala Arg Arg Lys Arg Ser Ala Gly Ala
305 310 315 320
Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe Glu Asp Ile
325 330 335
Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu Ala Tyr Glu
340 345 350
Cys Lys Gly Gly Cys Phe Phe Pro Leu Ala Asp Asp Val Thr Pro Thr
355 360 365
Lys His Ala Ile Val Gln Thr Leu Val His Leu Lys Phe Pro Thr Lys
370 375 380
Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro Ile Ser Val
385 390 395 400
Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr His Tyr Glu
405 410 415
Gly Met Ser Val Ala Glu Cys Gly Cys Arg Gly Gly Gly Gly Ser Gly
420 425 430
Gly Gly Gly Ser Gly Gly Gly Gly Ser His Thr Cys Pro Pro Cys Pro
435 440 445
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
450 455 460
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
465 470 475 480
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
485 490 495
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
500 505 510
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
515 520 525
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
530 535 540
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
545 550 555 560
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
565 570 575
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
580 585 590
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
595 600 605
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
610 615 620
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
625 630 635 640
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
645 650 655
Lys Ser Leu Ser Leu Ser Pro Gly Lys
660 665
Claims (14)
- 서열번호 2 내지 29로 구성된 군에서 선택되는 어느 하나의 아미노산 서열로 표시되는 골형성 단백질-9 (BMP-9) 변이체.
- 제1항의 BMP-9 변이체에 면역글로불린의 Fc 단편이 연결되어 있는 BMP-9 변이체-Fc 융합 단백질.
- 제2항에 있어서, 면역글로불린의 Fc 단편은 서열번호 30의 아미노산 서열로 표시되는 것을 특징으로 하는 BMP-9 변이체-Fc 융합 단백질.
- 제2항에 있어서, BMP-9 변이체; 및 면역글로불린의 Fc 단편은 링커에 의해 연결되어 있는 것을 특징으로 하는 BMP-9 변이체-Fc 융합 단백질.
- 제4항에 있어서, 상기 링커는 서열번호 31의 아미노산 서열로 표시되는 것을 특징으로 하는 BMP-9 변이체-Fc 융합 단백질.
- 제1항의 BMP-9 변이체; 또는 제2항 내지 제5항 중 어느 한 항의 BMP-9 변이체-Fc 융합 단백질을 유효성분으로 포함하는 종양 치료용 약학적 조성물.
- 제6항에 있어서, 상기 종양은 유방암, 폐암, 결장암, 대장암, 간암, 췌장암, 뇌종양, 전립선암, 피부암, 골육종 및 혈액암으로 구성된 군에서 선택되는 1종 이상인 것을 특징으로 하는 종양 치료용 약학적 조성물.
- 제1항의 BMP-9 변이체; 또는 제2항 내지 제5항 중 어느 한 항의 BMP-9 변이체-Fc 융합 단백질을 유효성분으로 포함하는 염증성 질환 치료용 약학적 조성물.
- 제8항에 있어서, 상기 염증성 질환은 지방간염, 간염 및 장염으로 구성된 군에서 선택된 1종 이상인 것을 특징으로 하는 염증성 질환 치료용 약학적 조성물.
- 제1항의 BMP-9 변이체; 또는 제2항 내지 제5항 중 어느 한 항의 BMP-9 변이체-Fc 융합 단백질을 유효성분으로 포함하는 대사성 질환 치료용 약학적 조성물.
- 제10항에 있어서, 상기 대사성 질환은 비만, 체중 감소, 당뇨병, 죽상경화증, 동맥경화증, 심폐질환, 신경 질환, 알츠하이머 질환, 인지 장애, 산화적 스트레스, 피부 질환, 피부 노화, UV 조사에 의한 손상, 고혈압, 고콜레스테롤혈증(LDL, HDL, VLDL), 고지혈증(트리글리세라이드), 면역 결핍, 암 및 대사성 증후군으로 구성된 군에서 선택된 1종 이상인 것을 특징으로 하는 대사성 질환 치료용 약학적 조성물.
- 제11항에 있어서, 상기 심폐질환은 심근경색, 고혈압, 폐동맥고혈압, 심근섬유증 및 폐섬유증으로 구성된 군에서 선택되는 1종 이상인 것을 특징으로 하는 대사성 질환 치료용 약학적 조성물.
- 제1항의 BMP-9 변이체; 또는 제2항 내지 제5항 중 어느 한 항의 BMP-9 변이체-Fc 융합 단백질을 유효성분으로 포함하는 자가면역 질환 치료용 약학적 조성물.
- 제13항에 있어서, 상기 자가면역 질환은 인슐린-의존성 당뇨병, 다발성 경화증, 자가면역 뇌척수염, 류마티스성 관절염, 골관절염, 중증 근무력증, 갑상선 염, 포도막염, 하시모토 갑상선염, 갑상샘 중독증, 악성 빈혈, 자가면역 위축 위염, 자가면역 용혈성 빈혈, 특발성 백혈구 감소, 원발성 담관 경화증, 알코올성/비알코올성 지방간염, 염증성 장질환, 크론병, 궤양성 장질환, 건선, 쇼그렌 증후군, 경피증, 베게너 육아종증, 다발근육염, 피부근육염, 원판상 LE 및 전신 홍반 루푸스로 구성된 군에서 선택된 1종 이상인 것을 특징으로 하는 자가면역 질환 치료용 약학적 조성물.
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KR1020200101759A KR20220021207A (ko) | 2020-08-13 | 2020-08-13 | 이소골 형성 부작용 경감으로 치료효과가 증진된 골형성 단백질-9, 10의 변이체 및 이를 포함하는 약학적 조성물 |
PCT/KR2021/010744 WO2022035260A1 (ko) | 2020-08-13 | 2021-08-12 | 이소골 형성 부작용 경감으로 치료효과가 증진된 골형성 단백질-9, 10의 변이체 및 이를 포함하는 약학적 조성물 |
US18/040,643 US20230272025A1 (en) | 2020-08-13 | 2021-08-12 | Bone morphogenetic protein-9 and -10 variants with enhanced therapeutic effect due to reduced side effects of ectopic ossification and pharmaceutical composition comprising same |
EP21856266.8A EP4198049A1 (en) | 2020-08-13 | 2021-08-12 | Bone morphogenetic protein-9 and -10 variants with enhanced therapeutic effect due to reduced side effects of heterotopic ossification and pharmaceutical composition comprising same |
JP2023510324A JP2023538013A (ja) | 2020-08-13 | 2021-08-12 | 異所性骨形成副作用の軽減で治療効果が増進した骨形成タンパク質-9、10の変異体及びこれを含む薬学的組成物 |
CN202180055774.2A CN116096396A (zh) | 2020-08-13 | 2021-08-12 | 由于异位骨化的副作用减少而具有增强的治疗效果的骨形态发生蛋白-9和骨形态发生蛋白-10变体以及包含所述变体的药物组合物 |
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EP2699590B8 (en) * | 2011-04-20 | 2019-04-17 | Acceleron Pharma Inc. | Endoglin polypeptides and uses thereof |
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JP2023538013A (ja) | 2023-09-06 |
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